Brain region may hold key to aging

While the search continues for the Fountain of Youth, researchers may have found the body's "fountain of aging": the brain region known as the hypothalamus. For the first time, scientists at Albert Einstein College of Medicine of Yeshiva University report that the hypothalamus of mice controls aging throughout the body. Their discovery of a specific age-related signaling pathway opens up new strategies for combating diseases of old age and extending lifespan. The paper was published today in the online edition of Nature.

"Scientists have long wondered whether aging occurs independently in the body's various tissues or if it could be actively regulated by an organ in the body," said senior author Dongsheng Cai, M.D., Ph.D., professor of molecular pharmacology at Einstein. "It's clear from our study that many aspects of aging are controlled by the hypothalamus. What's exciting is that it's possible—at least in mice—to alter signaling within the hypothalamus to slow down the aging process and increase longevity."

The hypothalamus, an almond-sized structure located deep within the brain, is known to have fundamental roles in growth, development, reproduction, and metabolism. Dr. Cai suspected that the hypothalamus might also play a key role in aging through the influence it exerts throughout the body.

"As people age," he said, "you can detect inflammatory changes in various tissues. Inflammation is also involved in various age-related diseases, such as metabolic syndrome, cardiovascular disease, neurological disease and many types of cancer." Over the past several years, Dr. Cai and his research colleagues showed that inflammatory changes in the hypothalamus can give rise to various components of metabolic syndrome (a combination of health problems that can lead to heart disease and diabetes).

To find out how the hypothalamus might affect aging, Dr. Cai decided to study hypothalamic inflammation by focusing on a protein complex called NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells). "Inflammation involves hundreds of molecules, and NF-κB sits right at the center of that regulatory map," he said.

In the current study, Dr. Cai and his team demonstrated that activating the NF-κB pathway in the hypothalamus of mice significantly accelerated the development of aging, as shown by various physiological, cognitive, and behavioral tests. "The mice showed a decrease in muscle strength and size, in skin thickness, and in their ability to learn—all indicators of aging. Activating this pathway promoted systemic aging that shortened the lifespan," he said.

Conversely, Dr. Cai and his group found that blocking the NF-κB pathway in the hypothalamus of mouse brains slowed aging and increased median longevity by about 20 percent, compared to controls.

The researchers also found that activating the NF-κB pathway in the hypothalamus caused declines in levels of gonadotropin-releasing hormone (GnRH), which is synthesized in the hypothalamus. Release of GnRH into the blood is usually associated with reproduction. Suspecting that reduced release of GnRH from the brain might contribute to whole-body aging, the researchers injected the hormone into a hypothalamic ventricle (chamber) of aged mice and made the striking observation that the hormone injections protected them from the impaired neurogenesis (the creation of new neurons in the brain) associated with aging. When aged mice received daily GnRH injections for a prolonged period, this therapy exerted benefits that included the slowing of age-related cognitive decline, probably the result of neurogenesis.

According to Dr. Cai, preventing the hypothalamus from causing inflammation and increasing neurogenesis via GnRH therapy are two potential strategies for increasing lifespan and treating age-related diseases. This technology is available for licensing.

More information: The title of the paper is "Hypothalamic Programming of Systemic Aging Involving IKKβ, NF-κB and GnRH." dx.doi.org/10.1038/nature12143

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Release of GnRH into the blood is usually associated with reproduction.

In my model of nutrient-dependent pheromone-controlled adaptive evolution, the epigenetic effects of olfactory/pheromonal input on hypothalamic GnRH pulse frequency and amplitude link ecological, social, neurogenic, and socio-cognitive niche construction (and nutrient stress or social stress) across species from microbes to man (e.g., starting with the control of feedback loops by the "alpha mating" pheromone of 'brewer's yeast. Does everyone understand that the production of the pheromones that control the molecular mechanisms of reproduction in all species is nutrient dependent? See Nutrient-dependent / Pheromone-controlled Adaptive Evolution. http://dx.doi.org...e.155672

I have the impression that evolutionary theorists think that all of the above is somehow controlled by mutations.

It makes evolutionary sense that "reduced release of GnRH from the brain might contribute to whole-body ageing." And "Release of GnRH into the blood is usually associated with reproduction." Viable reproduction is an evolutionary plus, and failure to be reproductive uses up resources the more reproductive members of a species need to survive. @JVK suggests that the "Release of GnRH into the blood" activating mechanism is pheromone response, which fits this picture well.

@JVK suggests that the "Release of GnRH into the blood" activating mechanism is pheromone response...

Thanks. To be clear, GnRH production is nutrient-dependent, which is why it is altered by associations with food odors (classical conditioning). Nutrient metabolism to pheromones that signal reproductive fitness control adaptive evolution (via classical conditioning) in my model: Human pheromones and food odors: epigenetic influences on the socioaffective nature of evolved behaviors, which was published last year in Socioaffective Neuroscience & Psychology http://dx.doi.org...i0.17338Nature article:"...we have focused on the hypothalamus, a key brain region that is crucial for the neuroendocrine interaction between the central nervous system and the periphery."

LeMagnen (1982)"The interaction between sensory inputs and hormonal levels appears to be a general rule in ... relationships underlying behavior." Olfacto endocrine relationships: past and future...

@JVK: I read your excellent paper (reference your last response) and had two thoughts:1- An article about Honey Bee colony collapse,http://phys.org/n...ide.htmlmay be related to your previous studies.2- Nutrient metabolism would include mastication, and this is immediately in proximity to the olfactory senses. Thus, one wonders what GnRH levels are in test animals w/o olfactory senses as compared to those with their normal olfactory senses. This would still retain the sense of taste, but might have different GnRH consequences.

Failed nutrient-dependent pheromone-controlled organism-level thermoregulation is responsible for collapse of populations, which makes it likely the cause of colony collapse in honeybees. The specific contributor may not be isolated, however, since it could be virtually any aspect of olfactory/pheromonal communication, which begins at the level of the microRNA / messenger RNA balance (i.e., long before we would see an epigentic effect on immune system function).

The point to be made however is in your 2- above. It is the sensory integration that must be modeled, starting with the chemical senses and moving forward across the life cycles of organisms that link the molecular mechanisms of species from microbes to man. Nutrient-dependent / Pheromone-controlled Adaptive Evolution http://dx.doi.org...e.155672Nutrient-dependent / Pheromone-controlled thermodynamics and thermoregulation http://dx.doi.org...e.643393